Participants Pregnant women in Denmark between 1997 and 2009 and their offspring.

Primary outcome measures For each SSRI, ORs for major congenital malformations were estimated using multivariable logistic regression models for women
exposed to an SSRI during the first trimester and for women with paused exposure during pregnancy.

Results The authors identified 848 786 pregnancies; 4183 were exposed to an SSRI throughout the first trimester and 806 pregnancies
paused exposure during pregnancy. Risks of congenital malformations of the heart were similar for pregnancies exposed to an
SSRI throughout the first trimester, adjusted OR 2.01 (95% CI 1.60 to 2.53), and for pregnancies with paused SSRI treatment
during pregnancy, adjusted OR 1.85 (95% CI 1.07 to 3.20), p value for difference: 0.94. The authors found similar increased
risks of specific congenital malformations of the heart for the individual SSRIs. Furthermore, the authors found no association
with dosage.

Conclusions The apparent association between SSRI use and congenital malformations of the heart may be confounded by indications. The
moderate absolute risk increase combined with uncertainty for causality still requires the risk versus benefit to be evaluated
in each individual case.

Contributors EJ-S, JTA and HEP conceptualised the study and MP, KB, JKJ, SA, GHG and CT-P assisted with the study design. EJ-S preformed
the analyses and JTA, MP, KB, CT-P and HEP assisted in the interpretation. EJ-S, JTA, MP, KB, JKJ, SA, GHG, CT-P and HEP wrote
and revised the article, as well as designed figures. All authors approved the final version to be published.

Funding The research project was partially sponsored by the Capital Region of Copenhagen and the Danish Agency for Science, Technology
and Innovation. Coverage of PhD enrolment fees.

Competing interests All authors declare no support from any organisation for the submitted work; no financial relationships with any organisations
that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could
appear to have influenced the submitted work.

Ethics approval The present study has been approved by the Danish Data Protection Agency (No. 2008-41-2517). Retrospective register studies
do not require ethical permission in Denmark.